Adiponectin receptor fragmentation in mouse models of type 1 and type 2 diabetes.
Adiponectin receptor fragmentation in mouse models of type 1 and type 2 diabetes.
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DOI：
10.46439/autoimmune.1.002
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发表时间：
2020
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影响因子：
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通讯作者：
Pugia MJ
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作者：
Frabutt D;Stull N;Pineros AR;Tersey SA;Scheuner D;Mastracci TL;Pugia MJ
蛋白质激素脂联素通过与两种PAQR家族受体（AdipoR 1和AdipoR 2）结合来调节葡萄糖和脂肪酸代谢。这两种受体都具有C-末端片段，其通过蛋白水解释放以形成在正常个体的血浆中发现的自由循环C-末端片段（CTF），但在一些未确定的糖尿病患者中不存在。AdipoR 1-CTF 344 -376是肿瘤坏死因子α裂解酶（TACE）的竞争性抑制剂，但它含有一个较短的肽结构域（AdipoR 1 CTF 351 -362），是胰岛素降解酶（IDE）的强非竞争性抑制剂。脂联素受体断裂和糖尿病病理之间的联系尚不清楚，但可能导致新的治疗策略。因此，我们研究了非肥胖糖尿病（NOD/ShiLtJ）小鼠和饮食诱导肥胖（DIO）的C57 BL/6小鼠中CTF浓度的生理变化，分别作为1型和2型糖尿病模型。我们检测了脂联素受体信号传导、免疫应答、疾病进展和中和自身抗体丰度的变化。最后，我们给予含有或缺乏IDE结合结构域的外源性AdipoR 1-CTF肽。我们在TACE活性NOD小鼠中观察到更明显的CTF脱落，这代表了炎性自身免疫表型，但在DIO模型中也观察到较小程度的碎片化。在两种模型中均检测到CTF自身抗体。外源性CTF肽均不影响IgG-CTF血浆水平、体重或NOD小鼠向糖尿病的转化。因此，在衰老、DIO和自身免疫性糖尿病的生理条件下，AdipoR 1片段化和自身抗体产生的模式提供了对脂联素生物学和糖尿病关联的深入了解。
The protein hormone adiponectin regulates glucose and fatty acid metabolism by binding to two PAQR-family receptors (AdipoR1 and AdipoR2). Both receptors feature a C-terminal segment which is released by proteolysis to form a freely circulating C-terminal fragment (CTF) found in the plasma of normal individuals but not in some undefined diabetes patients. The AdipoR1-CTF344–376 is a competitive inhibitor of tumor necrosis factor α cleavage enzyme (TACE) but it contains a shorter peptide domain (AdipoR1 CTF351–362) that is a strong non-competitive inhibitor of insulin-degrading enzyme (IDE). The link between adiponectin receptor fragmentation and diabetes pathology is unclear but could lead to new therapeutic strategies. We therefore investigated physiological variations in the concentrations of CTF in non-obese diabetic (NOD/ShiLtJ) mice and C57BL/6 mice with diet-induced obesity (DIO) as models of diabetes types 1 and 2, respectively. We tested for changes in adiponectin receptor signaling, immune responses, disease progression, and the abundance of neutralizing autoantibodies. Finally, we administered exogenous AdipoR1-CTF peptides either containing or lacking the IDE-binding domain. We observed the more pronounced CTF shedding in the TACE-active NOD mice, which represents an inflammatory autoimmune phenotype, but fragmentation was also observed to a lesser extent in the DIO model. Autoantibodies to CTF were detected in both models. Neither exogenous CTF peptide affected IgG-CTF plasma levels, body weight or the conversion of NOD mice to diabetes. The pattern of AdipoR1 fragmentation and autoantibody production under physiological conditions of aging, DIO, and autoimmune diabetes therefore provides insight into the association adiponectin biology and diabetes.